© 1998 American Heart Association, Inc.
Original Contributions |
Metabolic Determinants Are Much More Important Than Genetic Polymorphisms in Determining the PAI-1 Activity and Antigen Plasma Concentrations
A Family Study With Part of the Stanislas Cohort
From the Laboratoire Hématologie, CHU Timone, CJF INSERM, Marseille (M.H., M.C.A., M.F.A., I.J.-V.); INSERM U258, Paris (D.A.T., L.T.); and the Laboratoire Centre Médecine Préventive and Université Henri Poincaré, Vandoeuvre les Nancy (S.V., G.S.), France.
Correspondence to Prof I. Juhan-Vague, Laboratoire Hématologie, CHU Timone, 13385 Marseille Cedex 5, France.
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Abstract—Increased plasma plasminogen activator inhibitor-1 (PAI-1) concentration has been identified as a risk factor for coronary heart disease. We investigated the relative contribution of both metabolic factors involved in the insulin resistance (IR) syndrome and polymorphisms of the PAI-1 gene to plasma levels of PAI-1 in 228 healthy nuclear white families from the Stanislas Cohort. Variables related to IR included body mass index, waist-to-hip ratio, fasting insulin, triglyceride, and HDL cholesterol. Five PAI-1 gene polymorphisms were studied, including a newly described G+12078A substitution in the 3' region. A sex difference was observed, with fathers exhibiting higher IR state and PAI-1 levels and stronger correlations between PAI-1 and IR variables than mothers. Such a difference was not observed in offspring. Family correlations were of similar magnitude for fibrinolytic parameters and IR variables. The PAI-1 genotypes A-844G, -675 4G/5G, and G+12078A polymorphisms, which were in strong linkage disequilibrium, were associated with plasma PAI-1 levels. In multivariate analysis, IR explained a major part of PAI-1 variability (49% in fathers, 29% in mothers), whereas polymorphisms had only a minor contribution, explaining 3% of variability in women and having no significant effect in men. We conclude that plasma levels of PAI-1 are, in a healthy population, primarily determined by the IR syndrome, this relationship being stronger in males. The contribution of the PAI-1 gene seems larger in females. These results deserve special attention for understanding the relationships observed between fibrinolytic parameters and the risk of developing a cardiovascular ischemic event.
Key Words: plasminogen activator inhibitor 1 • risk factors • myocardial infarction • insulin resistance • genetics
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Introduction |
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Plasminogen activator inhibitor-1 is the primary inhibitor of both tPA and urokinase type plasminogen activator.1 2 The literature argues that PAI-1 is implicated in coronary heart disease (reviewed in Reference 33 ). Elevated PAI activity has been observed in patients with angina pectoris or a previous MI. High plasma PAI activity independently predicted reinfarction within 3 years of the primary event.4 The plasma concentration of PAI-1 was found to be a reliable predictor of coronary events in patients with angina pectoris.5 It was also recently shown that PAI-1 levels were related to the extent of vessel wall atherosclerosis.6
The level of PAI-1 can vary up to 100-fold among subjects. Its increase has been mainly considered as an acquired abnormality that would depend on an individual's insulin resistant or inflammatory status.5 7 Indeed, many cross-sectional studies have shown that plasma PAI-1 levels were strongly correlated with the cluster of variables defining the IR syndrome, such as BMI, WHR, fasting insulinemia, VLDL triglyceride, apolipoproteins A1 and B, and HDL cholesterol. PAI-1 levels have also been shown to correlate, but to a lesser extent, with fibrinogen.7 8 9 10 11 Some acute situations are also known to increase PAI-1 levels, such as alcohol consumption12 and acute infection.13
On the other hand, there is now accumulating evidence for a genetic control of circulating PAI-1. Eight different polymorphisms of the PAI-1 gene have been described so far: two (CA)n repeat polymorphisms, one in the promoter and one in intron 4,14 15 a HindIII restriction fragment length polymorphism,16 and an insertion (5G)/deletion (4G) polymorphism at position -675 of the PAI-1 promoter.17 In addition, our group has recently identified four other polymorphisms, two G-to-A substitutions at position -844 and +9785, a T-to-G substitution at position +11053, and a deletion of nine nucleotides from a threefold repeated sequence between nucleotides +11320 and 11345.18 Significant associations between some of these polymorphisms and plasma PAI-1 levels have been reported in non–insulin-dependent diabetics and in patients with MI.15 17 19 20 21 22 In healthy control subjects, associations did not always reach statistical significance.17 18 Some groups have observed a stronger association between plasma fibrinogen17 or triglyceride levels21 22 23 and plasma PAI activity in individuals homozygous for the -675 4G allele compared with 5G/5G subjects. Interestingly, the -675 4G allele frequency was significantly higher in a group of 100 Swedish MI patients aged 35 to 45 years than in control subjects.19 However, this relation was not confirmed in a larger case-control study including MI patients aged 25 to 6420 and in a large prospective study of healthy subjects followed up during 8 years.24 Allele frequency of the HindIII restriction fragment length polymorphism and the intron 4 (CA)n repeat did not differ between type 1 and 2 diabetics (with or without retinopathy) and control subjects.14
We report here the results of an association study carried in a sample of healthy families. This study was designed to determine the relative contribution of metabolic factors involved in the IR syndrome and of five polymorphisms of the PAI-1 gene to plasma levels of PAI-1 activity and antigen. The contribution to tPA antigen levels, reflecting mainly tPA/PAI-1 complexes, was also investigated.
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Family Data
The families were recruited between October 1993 and June 1994 in the Center for Preventive Medicine in Vandoeuvre lès Nancy, France, as a subsample of the 1000 families of the Stanislas cohort.25 The subsample included 228 nuclear families of white Europeans volunteering for a free health examination and having signed a statement of informed consent. Families were composed of both natural parents (n=456) and at least two offspring (n=511) aged more than 6 years. Exclusion criteria were presence of acute or chronic disease. All the members of the same family were examined on the same day. Information regarding smoking and diet habits, alcoholic beverages during the last 36 hours, drug intake, and medical history were obtained by questionnaires and interviews by physicians on the day of examination. Fasting blood samples were drawn after an overnight fast of >8 hours. Samples from the same family were processed together. Information on alcohol consumption was gathered by questionnaires and was calculated as grams of ethanol per day.
Anthropometric Parameters
BMI (weight [kg]/height [(m)2] was
calculated. Fat distribution was assessed as WHR, which is the ratio of
the circumference of the waist at the level of the umbilicus to that of
the hips at the level of the greater trochanters and the symphysis
pubis.
Fibrinolytic Parameters
Citrated blood was collected between 8 and 10 AM to
overcome the diurnal variation of PAI-1 and immediately processed.
After 30 minutes of centrifugation (2500g)
at 4°C, the middle layer of the plasma was rapidly pipetted off and
stored at -80°C. PAI-1 Act was assayed by a commercially available
kit (Spectrolyse/PL, Biopool), as were PAI-1 Ag (Asserachrom PAI-1,
Stago) and tPA Ag (Tintelize tPA, Biopool, which quantifies mainly
inactive tPA/PAI-1 complexes). The interassay coefficients of variation
were, respectively, 11%, 7%, and 8%.
Other Biological Parameters
Total cholesterol, HDL cholesterol,
triglycerides, apoB, apoA-I, and 
GT were determined by
routine clinical chemistry procedures. Plasma insulin was measured
using a commercially available radioimmunoassay kit (CEA SORIN).
Fibrinogen concentration was determined in citrated plasma by the
Clauss thrombin clotting method.26 The interassay
coefficients of variation for these assays were, respectively, 1.7%,
5.2%, 4.2%, 6.6%, 7.9%, 4.5%, 5%, and 3.3%.
Detection of the Polymorphisms of the PAI-1 Gene
The genomic DNA was prepared by standard salting-out
techniques.27 The sets of primers used for
amplification of relevant DNA regions, the probes, and the methods used
to detect the PAI-1 polymorphisms have been previously
described.18 Briefly, the genotypes
resulting from the G-to-A substitution at position -844 were assessed
by Xho 1 endonuclease digestion.
The genotypes for the insertion/deletion polymorphism (4G/5G) at position -675, the G-to-A substitution at position +9785, and the T-to-G substitution at position +11053 were analyzed by allele-specific oligonucleotide hybridization using biotinylated probes.
An additional polymorphism has been recently found by our group in the 3' untranslated region of the gene. It is localized just before the two potential polyadenylation signals for the 3.2-kb mRNA specie. It corresponds to a G-to-A substitution in position +12078, which creates an Acc I restriction site. This sequence variation was evidenced by a shift of migration in nonisotopic polymerase chain reaction SSCP electrophoresis in 5% PAA 10% glycerol gel, in the conditions previously described.18 It was confirmed by direct sequencing of polymerase chain reaction samples. This polymorphism was genotyped by Acc I restriction analysis. The endonuclease digestion of the polymerase chain reaction fragment gave two fragments of 247 and 77 bp when the A allele was present.
Statistical Analysis
Since individuals within a family are not independent,
conventional statistical procedures could not be used. Statistical
analyses were carried out using the estimating equations
technique proposed by Liang and Zeger.28 We
developed an application of this technique for studying association
between genetic markers and phenotypes using family
data.29 This method provides asymptotically
unbiased estimates of association parameters and of their
standard errors. Association is then tested by means of a Wald
test.
Plasma levels of PAI-1 Act, PAI-1 Ag, tPA Ag, insulin,
triglycerides, and GT were log transformed to remove
positive skewness. PAI-1 Act, PAI-1 Ag, and tPA Ag levels were adjusted
on age and, in women, on oral contraception before analysis,
separately in each group of relatives (fathers, mothers, sons, and
daughters). Pearson correlation coefficients were calculated between
fibrinolytic parameters and metabolic factors
in each group of relatives, and homogeneity of association according to
gender was tested by comparing regression slopes between fathers and
mothers and between sons and daughters, respectively. Age- and
sex-adjusted family correlations for fibrinolytic and
metabolic parameters were estimated by using a
maximum-likelihood method.30
Hardy-Weinberg equilibrium for each polymorphism of the PAI-1 gene
was tested in parents by a 
2 test with
one df. Pairwise linkage disequilibrium coefficients between
polymorphisms were estimated using a log-linear model
analysis,31 and the extent of
disequilibrium was expressed in terms of D'D/Dmax or
-D/Dmin.
Association between fibrinolytic parameters and
polymorphisms of the PAI-1 gene was investigated by linear
regression analysis. Homogeneity of association between
fibrinolytic parameters and other factors (eg,
triglycerides) across genotypes was tested by
comparing genotype-specific regression slopes. Finally,
multivariate regression analysis was performed
to evaluate the relative contribution of metabolic factors
and polymorphisms of the PAI-1 gene to the variability of
fibrinolytic parameters in each group of relatives. The
contribution of polymorphisms to PAI-1 and tPA variability
(R2) was calculated as the proportion of
variance explained by PAI-1 genotypes before (Table 6
) or after
(Table 8) controlling for metabolic factors.
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Results |
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The characteristics of the population studied are given in Table 1
. Fathers were older than mothers and
exhibited higher alcohol consumption, GT levels, numbers of
cigarettes smoked, and more pronounced features of the IR syndrome,
with higher BMI, WHR, triglycerides, total
cholesterol, apoB, and insulin levels and lower HDL
cholesterol and apoA-I levels. Fathers also had strongly
higher mean PAI-1 and tPA levels than mothers. In both genders, PAI-1
and tPA levels increased with age (Fig 1). After adjustment of IR variables,
the sex difference in mean PAI-1 and tPA levels was no longer
significant. No such differences according to sex were observed in
offspring, except for WHR, HDL cholesterol, apoA-I, and
GT. When considering the offspring population as a whole, plasma
levels of PAI-1 and tPA did not differ between sexes (Table 1).
Actually, this lack of global difference in children reflected
different patterns of variations with age: concentrations were slightly
higher in girls than in boys before puberty but decreased after puberty
in girls (Fig 1).
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Age-adjusted correlations of PAI-1 and tPA levels with biological and
anthropometric parameters were calculated in each group of
relatives (Table 2). Correlations of
PAI-1 Ag and tPA Ag with the different variables paralleled
those observed on PAI-1 Act and are not reported. As expected, PAI-1
and tPA were strongly correlated to each other and to the variables
of the IR syndrome. PAI-1 showed closer relationships with most of the
metabolic factors than did tPA (data not shown). Fathers
exhibited stronger correlations between PAI-1 and the IR variables
than did mothers. The same tendency was observed for tPA, although the
difference of correlations between sexes failed to reach significance.
In offspring, correlations between PAI-1 and tPA were weaker than in
adults. Correlations between fibrinolytic and IR variables were of
similar magnitude between sons and daughters, except for the PAI-1xWHR
and the tPAxinsulin correlations, which were stronger in sons.
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PAI-1 and tPA also significantly correlated with GT, primarily in
fathers. Adjustment for alcohol consumption did not reduce this
association, since alcohol consumption did not significantly influence
PAI-1 or tPA levels (Table 2
). Alcohol consumption also was not related
to IR variables (data not shown). By contrast, GT strongly
correlated with IR variables in fathers (BMI r=.34, WHR
r0.38, insulin r=.37, and
triglyceride r=.35; P<.0001).
Fibrinogen levels weakly correlated with tPA (r=.19 in fathers and .24 in mothers) and were not associated with PAI-1 levels in this healthy population.
Family correlations of fibrinolytic and metabolic
variables are given in Table 3.
Spouses exhibited a significant resemblance for all
parameters. For metabolic factors, correlations
between biological relatives were generally higher than correlations
between spouses. For none of these factors did the sib-sib correlation
significantly differ from the parent-offspring correlation. For PAI-1
Act as well as PAI-1 Ag, all correlations between family members were
of similar magnitude. For tPA Ag, sibs exhibited a greater resemblance
with each other than did parents and offspring (P=.03).
Adjustment of IR variables hardly modified family correlations of
fibrinolytic parameters (data not shown).
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Associations Between PAI-1 Gene Polymorphisms and Levels of
Fibrinolytic Parameters
Allele frequencies and linkage disequilibrium between
polymorphisms are given in Table 4.
All genotype distributions were compatible with Hardy-Weinberg
equilibrium in parents. As previously shown,18
the A/G substitution at position -844 and the 4G/5G polymorphism
at position -675 were in nearly complete association. The G-to-A
substitution at position +9785 was in quasicomplete negative
disequilibrium with the T-to-G substitution at position +11053 and the
newly described G-to-A substitution at position +12078. This latter
polymorphism in the 3' untranslated region was in strong positive
linkage disequilibrium with the two polymorphisms of the promoter
region.
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Associations between polymorphisms of the PAI-1 gene and plasma
levels of the fibrinolytic parameters are presented
in Table 5. Considering the entire
population, the -675 4G/5G polymorphism was significantly
associated with the three measured fibrinolytic parameters,
explaining between 1.1% and 2.2% of their respective variances in the
whole population after adjustment for class of relatives, age, and
contraception. For all three parameters, the -675 5G5G
genotype was associated with lower plasma levels.
Consistent with the tight association existing between -675
4G/5G and A-844G, the -844 GG genotype was also associated
with decreased levels of fibrinolytic parameters. The
association was, however, weaker than with the -675 4G/5G
polymorphism and even failed to reach significance for PAI-1 Act.
The G+12078A polymorphism in the 3' region was also associated with
PAI-1 Ag and tPA Ag, the A allele being associated with decreased
levels in a fairly additive fashion. No relationship was observed
either with the G+9785A or with the T+11053G polymorphism. Because
of the strong linkage disequilibrium existing within the PAI-1 gene, we
also examined the role of polymorphisms considered by pairs to
detect possible combinations of genotypes that would be more
strongly associated with PAI-1 levels, but no such combination could be
identified.
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We further examined associations of polymorphisms of the PAI-1 gene
with fibrinolytic parameters in each group of relatives
(Table 6). Results of the A-844G and
G+12078A polymorphisms are not reported because they paralleled
those observed with the -675 4G/5G polymorphism, although the
significance of association was generally lower. Although the -675
5G/5G genotype displayed lower levels of PAI-1 and tPA levels
in all groups of relatives, the association was significant only in
mothers and daughters. In mothers, PAI-1 levels appeared slightly
higher in 4G/5G heterozygotes than in 4G/4G homozygotes, but this
difference was not statistically significant. By contrast, PAI-1 levels
were significantly lower in 5G/5G homozygotes compared with other
subjects. Likewise, the decreasing effect of the -844G allele and
the +12078A allele on PAI-1 Ag and tPA Ag found in the whole
population was observed in each group of relatives, but did not always
reach significance. Some weak associations between fibrinolytic
variables and the T+11053G polymorphism were also observed,
although not consistently, whereas there was a lack of
association with the G+9785A polymorphism.
Correlations Between PAI-1 Act, PAI-1 Ag, tPA Ag, and
Triglycerides by -675 4G/5G and G+12078A
Genotypes
Since the association between PAI-1 and triglycerides
has been previously reported to differ according to genotype,
we looked at the correlations between the three fibrinolytic
parame-ters and triglycerides by -675 4G/5G, A
-844 G, and G+12078A genotypes. No significant
heterogeneity could be detected in any group of
relatives (Table 7). No significant interaction could be detected with
any other metabolic factor.
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Contribution of metabolic factors and polymorphisms
of the PAI-1 gene to the variability of PAI-1 Act, PAI-1 Ag, and tPA Ag
(Results are presented in Table 8)
IR variables explained a major part of the variability of
PAI-1 Act and Ag levels, the highest contribution (49%) being
observed in fathers. After adjustment for IR variables, the -675
4G/5G polymorphism had a modest effect on PAI-1 levels, explaining
about 3% of the variance in mothers and daughters and being
nonsignificant in fathers and sons. The influence of
metabolic factors on tPA antigen was less pronounced than
for PAI-1 Act and Ag, especially in fathers. After adjustment for
metabolic factors, the -675 4G/5G polymorphism
remained significantly associated with tPA only in mothers,
contributing to 5.6% of the phenotype variability in this
group. When compared with the R2 from
univariate analyses (Table 6), it appeared that
all associations were reduced after adjustment for
metabolic factors and even lost significance for the
G+12078A polymorphism.
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Discussion |
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Our study was undertaken to investigate the respective contribution of metabolic parameters, primarily those included in the IR syndrome, and PAI-1 genotypes to the variability of plasma PAI-1 levels. This evaluation may improve our understanding of circulating PAI-1 regulation and allow identification of means to reduce the plasma level of PAI-1, a possible contributing factor to coronary artery disease. For this purpose, plasma PAI-1 and tPA levels were both measured in a sample of healthy nuclear families, and their association with five polymorphisms of the PAI-1 gene were investigated.
As generally reported, PAI-1 and tPA levels were higher in men than in women.32 33 34 But interestingly, this sexual difference was, in our study, exclusively noted in adults and not in offspring. As our group and subsequently other investigators have already demonstrated in various groups of patients,7 8 9 10 11 PAI-1 levels were in strong correlation with all the variables of the IR syndrome. These relationships were more pronounced in fathers than in mothers. The same tendency was observed in offspring, as correlation coefficients were significantly higher in sons than in daughters for WHR (for PAI-1) and insulin (for tPA Ag). After adjustment of IR variables, the sex difference of PAI-1 and tPA levels was no longer significant. This result argues in favor of a strong influence of the IR process on PAI-1 production. Among several experimental attempts to unravel this mechanism, the recent demonstration of a PAI-1 production by visceral fat in rats35 and humans36 could be of particular relevance. Indeed, central fat accumulation is a characteristic feature of IR, and it is more often encountered in men.37 38 It is interesting to note that in a small family study of non–insulin-dependent diabetic patients, PAI-1 levels were elevated in relatives of diabetic subjects and remained higher than in control subjects even after adjustment for some IR markers and the PAI-1 promoter genotype -675 4G/5G.39 The apparent discrepancy with our findings could be explained by differences in the markers of IR entered in the regression model.
The observed sexual and age differences could also suggest an influence of sexual hormones in circulating PAI-1 levels. Some studies have already shown that testosterone is associated with plasma PAI-1 levels and might influence its circulating level.40 41 42 43 Testosterone does not seem to directly influence circulating PAI-1, as decrease in PAI-1 has been obtained without modification of testosterone.44 An indirect association through obesity might be more relevant. Indeed, it has been demonstrated that testosterone influences lipid accumulation, and particularly visceral fat accumulation.45 A lowering effect of estrogen on plasma PAI-1 and tPA levels has also been proposed.46 Our results showing a decrease of PAI-1 and tPA levels in daughters after puberty would be compatible with this hypothesis.
Another contribution to the higher PAI-1 and tPA levels observed in
fathers might be that they were subjected to a particular environment.
Smoking in this study had no influence on PAI-1 levels. A weak but
nonsignificant relation was observed between alcohol consumption and
PAI-1 levels. On the other hand, GT levels were positively
correlated with all three fibrinolytic parameters, as
previously reported.47 48 Although GT is
generally used as a marker of alcohol intake, within its normal range,
it reflects many other factors besides alcohol consumption, in
particular the BMI.49 50 In the present
population, the correlations between fibrinolytic
parameters and GT levels are then a reflection of the IR
status rather than of alcohol consumption.
PAI-1 levels observed in fathers were comparable with males of other French populations drawn from the ECTIM study.20
The pattern of family resemblance observed for metabolic parameters, with a higher degree of resemblance between biological relatives than between spouses, supported evidence for a genetic component of the IR syndrome, even though the influence of common lifestyle factors was also attested to by significant correlations between spouses. By contrast, the similarity of correlations between spouses and biological relatives for PAI-1 levels, as well as the rather strong resemblance between spouses, suggested a weaker impact of genetic factors than for metabolic factors and a greater influence of shared environment. However, it should also be stressed again that all members of a family were examined on the same day and blood samples processed together, which might have induced an overestimation of family correlations.
Besides being influenced by metabolic status, plasma PAI-1 levels have been shown to vary according to PAI-1 genotypes.15 16 17 19 20 21 In the present study, three of the five polymorphisms investigated were found associated with plasma PAI-1 levels, two of which were located in the promoter region, A-844G and -675 4G/5G, and one in the 3' region, G+12078A. By contrast, the G +9785A and T +11053G polymorphisms did not display any significant association with PAI-1 levels in this population. Because of the tight association existing between A-844G and -675 4G/5G, it was not possible to disentangle their respective influence on PAI-1 levels. It has been demonstrated that alleles of the -675 4G/5G polymorphism bound differently to nuclear factors.17 19 On the other hand, the A-844G is located in a potential Ets protein DNA binding sequence, which could be implicated in PAI-1 gene transcription. The G+12078A polymorphism is also in strong linkage disequilibrium with these two polymorphisms, which makes it difficult to assess whether it has a contribution to the PAI-1 variability. At any rate, this contribution seemed quite modest and was no longer significant after adjustment of metabolic factors. Its location in the 3' region might lead to the hypothesis that it is involved in the posttranscriptional regulation of the PAI-1 gene.51 Surprisingly, tPA levels were also associated with PAI-1 genotypes and sometimes more closely than PAI-1 levels. An explanation could be that tPA Ag reflects mainly tPA/PAI-1 complexes and is primarily indicative of variations of the circulating PAI-1.52
Compared with the large fraction explained by metabolic factors, the -675 4G/5G polymorphism had only a modest contribution to PAI-1 and tPA variability, explaining 3% to 5% of the interindividual variation of circulating PAI-1 and tPA levels in females and having no significant contribution in males. One explanation for this difference between sexes could be a regulation of the PAI-1 gene by sexual hormones. Another explanation, being plausible at least in parents, was that the overall variability of PAI-1 levels was considerably higher in fathers than in mothers, in part due to a greater influence of measured metabolic factors, which might have obscured relatively modest genetic effects. The small effect imparted could explain why the association of plasma PAI-1 activity level with the -675 4G/5G polymorphism was found in some studies19 20 21 but not in others.17 18 22 In these latter studies, it can be emphasized that the populations were exclusively constituted of healthy men, as in our study.
A significant interaction has been described between PAI-1 4G/5G genotypes and serum triglycerides in non–insulin-dependent diabetic patients21 22 and in patients undergoing coronary angiography,23 with a steeper slope in the 4G/4G genotype. Such an interaction was not demonstrated in patients with previous MI or in healthy control subjects.20 Neither was it found in our healthy population, although in males, the correlation between PAI-1 and triglyceride levels actually tended to be increased in carriers of the -675 4G allele. Such an interaction, if confirmed in larger studies, would indicate that genetic effects are more likely to be detected in hypertriglyceridemic subjects, such as diabetic patients, than in healthy subjects.
In conclusion, this study, conducted in a healthy population, suggests that metabolic factors involved in the IR syndrome are the primary determinants of plasma PAI-1 and tPA levels, whereas polymorphisms of the PAI-1 gene have a modest contribution to the variability of these fibrinolytic parameters. Further studies are needed to better understand the mechanisms of regulation of the PAI-1 gene, in particular those related to sex, as well as those involved in pathological conditions known to increase PAI-1 levels, such as non–insulin-dependent diabetes, inflammation, or sepsis.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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The Stanislas cohort is supported regularly by Beckman instruments, Biomerieux, Johnson and Johnson, and Merck. This work was supported by grants from INSERM (CJF 93/12) and from the Ministère du Travail et des Affaires Sociales, Direction des Hôpitaux, Programme Hospitalier de Recherche Clinique (PHRC), and from the Ministère de l'Education Nationale, de l'Enseignement Supérieure de la Recherche et de l'Insertion Professionnelle (programme quadriennal, Université de la Méditerranée).
Received June 17, 1997; accepted September 22, 1997.
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